METHODS AND MATERIALS FOR DETERMINING pGC TARGET DOSAGE

Abstract

Methods and materials for assessing therapeutic efficacy with particulate guanylyl cyclase (pGC) receptor stimulators are provided herein. Also provided herein are methods and materials for administering pGC receptor stimulators to mammals based on the assessment.

1 . A method for determining whether a mammal having a cardiovascular, cardiorenal, or cardiometabolic disorder is likely to be responsive to treatment with a particulate guanylate cyclase (pGC) receptor stimulator, said method comprising:
 (a) contacting, with a first biological fluid sample from said mammal, a first population of cells that express a pGC-A receptor, a pGC-B receptor, or both a pGC-A receptor and a pGC-B receptor, and measuring a first amount of cGMP produced by said first population of cells after said contacting;   (b) contacting a second population of said cells that express a pGC-A receptor, a pGC-B receptor, or both a pGC-A receptor and a pGC-B receptor, with a second biological fluid sample from said mammal in combination with said pGC receptor stimulator, and measuring a second amount of cGMP produced by said second population of cells after said contacting;   (c) comparing said first amount of cGMP to said second amount of cGMP; and   (d) when said second amount of cGMP is at least 5% greater than said first amount of cGMP, classifying said mammal as likely to respond to said pGC receptor stimulator, or when said second amount of cGMP is not at least 5% greater than said first amount of cGMP, classifying said mammal as not likely to respond to treatment with said pGC receptor stimulator.   
     
     
         2 . The method of  claim 1 , wherein said mammal is a human. 
     
     
         3 . The method of  claim 1 , wherein said cardiovascular, cardiorenal, or cardiometabolic disorder comprises heart failure (HF), hypertension (HT), cardiorenal syndrome, chronic kidney disease, metabolic syndrome, acute kidney injury, acute kidney disease, or cardiomyopathy. 
     
     
         4 . The method of  claim 3 , wherein said HF is acute decompensated heart failure (ADHF), HF with reduced ejection fraction, or HF with preserved ejection fraction, or wherein said HT is primary HT, uncontrolled HT, resistant HT, or pulmonary HT. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein said biological fluid sample is a blood sample or a plasma sample. 
     
     
         7 . The method of  claim 1 , comprising incubating said first and second populations of cells with said first and second biological fluid samples for at least 10 minutes before measuring said first and second amounts of cGMP. 
     
     
         8 . The method of  claim 1 , wherein said pGC receptor stimulator is selected from the group consisting of MANP, C53, CRRL-408, MCUF-651, vosoritide, nesiritide, carperitide, cenderitide, and neprilysin inhibitors. 
     
     
         9 . A method for treating a mammal having a cardiovascular, cardiorenal, or cardiometabolic disorder, said method comprising:
 (a) contacting, with a first biological fluid sample from said mammal, a first population of cells that express a pGC-A receptor, a pGC-B receptor, or both a pGC-A receptor and a pGC-B receptor, and measuring a first amount of cGMP produced by said first population of cells after said contacting;   (b) contacting a second population of said cells that express a pGC-A receptor, a pGC-B receptor, or both a pGC-A receptor and a pGC-B receptor, with a second biological fluid sample from said mammal in combination with a pGC receptor stimulator, and measuring a second amount of cGMP produced by said second population of cells after said contacting;   (c) comparing said first amount of cGMP to said second amount of cGMP; and   (d) administering said pGC receptor stimulator to said mammal when said second amount of cGMP is at least 5% greater than said first amount of cGMP.   
     
     
         10 . The method of  claim 9 , wherein said mammal is a human. 
     
     
         11 . The method of  claim 9 , wherein said cardiovascular, cardiorenal, or cardiometabolic disorder comprises HF, HT, cardiorenal syndrome, chronic kidney disease, metabolic syndrome, acute kidney injury, acute kidney disease, or cardiomyopathy. 
     
     
         12 . The method of  claim 11 , wherein said HF is ADHF, HF with reduced ejection fraction, or HF with preserved ejection fraction, or wherein said HT is primary HT, uncontrolled HT, resistant HT, or pulmonary HT. 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 9 , wherein said biological fluid sample is a blood sample or a plasma sample. 
     
     
         15 . The method of  claim 9 , comprising incubating said first and second populations of cells with said first and second biological fluid samples for at least 10 minutes before measuring said first and second amounts of cGMP. 
     
     
         16 . The method of  claim 9 , wherein said pGC receptor stimulator is selected from the group consisting of MANP, C53, CRRL-408, MCUF-651, vosoritide, nesiritide, carperitide, cenderitide, and neprilysin inhibitors. 
     
     
         17 . A method for treating a mammal having a cardiovascular, cardiorenal, or cardiometabolic disorder, said method comprising administering a pGC receptor stimulator to said mammal, wherein said mammal was identified being in need of said pGC receptor stimulator based on a method comprising:
 (a) contacting, with a first biological fluid sample from said mammal, a first population of cells that express a pGC-A receptor, a pGC-B receptor, or both a pGC-A receptor and a pGC-B receptor, and measuring a first amount of cGMP produced by said first population of cells after said contacting;   (b) contacting a second population of said cells that express a pGC-A receptor, a pGC-B receptor, or both a pGC-A receptor and a pGC-B receptor, with a second biological fluid sample from said mammal in combination with said pGC receptor stimulator, and measuring a second amount of cGMP produced by said second population of cells after said contacting;   (c) comparing said first amount of cGMP to said second amount of cGMP; and   (d) determining that said second amount of cGMP is at least 5% greater than said first amount of cGMP.   
     
     
         18 . The method of  claim 17 , wherein said mammal is a human. 
     
     
         19 . The method of  claim 17 , wherein said cardiovascular, cardiorenal, or cardiometabolic disorder comprises HF, HT, cardiorenal syndrome, chronic kidney disease, metabolic syndrome, acute kidney injury, acute kidney disease, or cardiomyopathy. 
     
     
         20 . The method of  claim 19 , wherein said HF is ADHF, HF with reduced ejection fraction, or HF with preserved ejection fraction, or wherein said HT is primary HT, uncontrolled HT, resistant HT, or pulmonary HT. 
     
     
         21 . (canceled) 
     
     
         22 . The method of  claim 17 , wherein said biological fluid sample is a blood sample or a plasma sample. 
     
     
         23 . The method of  claim 17 , wherein said cells were incubated with said biological fluid sample for at least 10 minutes before measuring said amount of cGMP. 
     
     
         24 . The method of  claim 17 , wherein said pGC receptor stimulator is selected from the group consisting of MANP, C53, CRRL-408, MCUF-651, vosoritide, nesiritide, carperitide, cenderitide, and neprilysin inhibitors.